Human Temporal Cortex Research Articles

Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

IntroductionPhospholipase D (PLD), a lipolytic enzyme that breaks down membrane phospholipids, is also involved in signaling mechanisms downstream of seven transmembrane receptors. Abnormally elevated levels of PLD activity are well-established in Alzheimer's disease (AD), implicating the two isoforms of mammalian phosphatidylcholine cleaving PLD (PC-PLD1 and PC-PLD2). Therefore, we took a systematic approach of investigating isoform-specific expression in human synaptosomes and further investigated the possibility of therapeutic intervention using preclinical studies. MethodsSynaptosomal Western blot analyses on the postmortem human hippocampus, temporal cortex, and frontal cortex of AD patient brains/age-matched controls and the 3XTg-AD mice hippocampus (mouse model with overexpression of human amyloid precursor protein, presenilin-1 gene, and microtubule-associated protein tau causing neuropathology progressing comparable to that in human AD patients) were used to detect the levels of neuronal PLD1 expression. Mouse hippocampal long-term potentiation of PLD1-dependent changes was studied using pharmacological approaches in ex vivo slice preparations from wild-type and transgenic mouse models. Finally, PLD1-dependent changes in novel object recognition memory were assessed following PLD1 inhibition. ResultsWe observed elevated synaptosomal PLD1 in the hippocampus/temporal cortex from postmortem tissues of AD patients compared to age-matched controls and age-dependent hippocampal PLD1 increases in 3XTg-AD mice. PLD1 inhibition blocked effects of oligomeric amyloid β or toxic oligomeric tau species on high-frequency stimulation long-term potentiation and novel object recognition deficits in wild-type mice. Finally, PLD1 inhibition blocked long-term potentiation deficits normally observed in aging 3XTg-AD mice. DiscussionUsing human studies, we propose a novel role for PLD1-dependent signaling as a critical mechanism underlying oligomer-driven synaptic dysfunction and consequent memory disruption in AD. We, further, provide the first set of preclinical studies toward future therapeutics targeting PLD1 in slowing down/stopping the progression of AD-related memory deficits as a complementary approach to immunoscavenging clinical trials that are currently in progress.

High-Throughput Data of Circular RNA Profiles in Human Temporal Cortex Tissue Reveals Novel Insights into Temporal Lobe Epilepsy

Background/Aims: Circular RNAs (circRNAs) are a class of long noncoding RNAs with a closed loop structure that regulate gene expression as microRNA sponges. CircRNAs are more enriched in brain tissue, but knowledge of the role of circRNAs in temporal lobe epilepsy (TLE) has remained limited. This study is the first to identify the global expression profiles and characteristics of circRNAs in human temporal cortex tissue from TLE patients. Methods: Temporal cortices were collected from 17 TLE patients and 17 non-TLE patients. Total RNA was isolated, and high-throughput sequencing was used to profile the transcriptome of dysregulated circRNAs. Quantitative PCR was performed for the validation of changed circRNAs. Results: In total, 78983 circRNAs, including 15.29% known and 84.71% novel circRNAs, were detected in this study. Intriguingly, 442 circRNAs were differentially expressed between the TLE and non-TLE groups (fold change≥2.0 and FDR≤0.05). Of these circRNAs, 188 were up-regulated, and 254 were down-regulated in the TLE patient group. Eight circRNAs were validated by real-time PCR. Remarkably, circ-EFCAB2 was intensely up-regulated, while circ-DROSHA expression was significantly lower in the TLE group than in the non-TLE group (P<0.05). Bioinformatic analysis revealed that circ-EFCAB2 binds to miR-485-5p to increase the expression level of the ion channel CLCN6, while circ-DROSHA interacts with miR-1252-5p to decrease the expression level of ATP1A2. Conclusions: The dysregulations of circRNAs may reflect the pathogenesis of TLE and circ-EFCAB2 and circ-DROSHA might be potential therapeutic targets and biomarkers in TLE patients.

Loss of constitutive functional γ-aminobutyric acid type A-B receptor crosstalk in layer 5 pyramidal neurons of human epileptic temporal cortex.

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in adult central nervous system, and profound alterations of GABA receptor functions are linked to temporal lobe epilepsy (TLE). Here we describe the functional relationships between GABA receptors type B (GABAB R) and type A (GABAA R) in human temporal cortex and how TLE affects this aspect of GABAergic signaling. Miniature inhibitory postsynaptic currents (mIPSCs) were recorded by patch-clamp techniques from human L5 pyramidal neurons in slices from temporal cortex tissue obtained from surgery. We describe a constitutive functional crosstalk between GABAB Rs and GABAA Rs in human temporal layer 5 pyramidal neurons, which is lost in epileptic tissues. The activation of GABAB Rs by baclofen, in addition to the expected reduction of mIPSC frequency, produced, in cortex of nonepileptic patients, the prolongation of mIPSC rise and decay times, thus increasing the inhibitory net charge associated with a single synaptic event. Block of K+ channels did not prevent the increase of decay time and charge. Protein kinase A (PKA) blocker KT5720 and pertussis toxin inhibited the action of baclofen, whereas 8Br-cAMP mimicked the GABAB R action. The same GABAB R-mediated modulation of GABAA Rs was observed in pyramidal neurons of rat temporal cortex, with both PKA and PKC involved in the process. In cortices from TLE patients and epileptic rats, baclofen lost its ability to modulate mIPSCs. Our results highlight the association of TLE with functional changes of GABAergic signaling that may be related to seizure propagation, and suggest that the selective activation of a definite subset of nonpresynaptic GABAB Rs may be therapeutically useful in TLE.

Relating dynamic brain states to dynamic machine states: Human and machine solutions to the speech recognition problem.

There is widespread interest in the relationship between the neurobiological systems supporting human cognition and emerging computational systems capable of emulating these capacities. Human speech comprehension, poorly understood as a neurobiological process, is an important case in point. Automatic Speech Recognition (ASR) systems with near-human levels of performance are now available, which provide a computationally explicit solution for the recognition of words in continuous speech. This research aims to bridge the gap between speech recognition processes in humans and machines, using novel multivariate techniques to compare incremental ‘machine states’, generated as the ASR analysis progresses over time, to the incremental ‘brain states’, measured using combined electro- and magneto-encephalography (EMEG), generated as the same inputs are heard by human listeners. This direct comparison of dynamic human and machine internal states, as they respond to the same incrementally delivered sensory input, revealed a significant correspondence between neural response patterns in human superior temporal cortex and the structural properties of ASR-derived phonetic models. Spatially coherent patches in human temporal cortex responded selectively to individual phonetic features defined on the basis of machine-extracted regularities in the speech to lexicon mapping process. These results demonstrate the feasibility of relating human and ASR solutions to the problem of speech recognition, and suggest the potential for further studies relating complex neural computations in human speech comprehension to the rapidly evolving ASR systems that address the same problem domain.

Comprehensive Morpho-Electrotonic Analysis Shows 2 Distinct Classes of L2 and L3 Pyramidal Neurons in Human Temporal Cortex.

There have been few quantitative characterizations of the morphological, biophysical, and cable properties of neurons in the human neocortex. We employed feature-based statistical methods on a rare data set of 60 3D reconstructed pyramidal neurons from L2 and L3 in the human temporal cortex (HL2/L3 PCs) removed after brain surgery. Of these cells, 25 neurons were also characterized physiologically. Thirty-two morphological features were analyzed (e.g., dendritic surface area, 36 333 ± 18 157 μm2; number of basal trees, 5.55 ± 1.47; dendritic diameter, 0.76 ± 0.28 μm). Eighteen features showed a significant gradual increase with depth from the pia (e.g., dendritic length and soma radius). The other features showed weak or no correlation with depth (e.g., dendritic diameter). The basal dendritic terminals in HL2/L3 PCs are particularly elongated, enabling multiple nonlinear processing units in these dendrites. Unlike the morphological features, the active biophysical features (e.g., spike shapes and rates) and passive/cable features (e.g., somatic input resistance, 47.68 ± 15.26 MΩ, membrane time constant, 12.03 ± 1.79 ms, average dendritic cable length, 0.99 ± 0.24) were depth-independent. A novel descriptor for apical dendritic topology yielded 2 distinct classes, termed hereby as “slim-tufted” and “profuse-tufted” HL2/L3 PCs; the latter class tends to fire at higher rates. Thus, our morpho-electrotonic analysis shows 2 distinct classes of HL2/L3 PCs.

How Auditory Experience Differentially Influences the Function of Left and Right Superior Temporal Cortices.

To investigate how hearing status, sign language experience, and task demands influence functional responses in the human superior temporal cortices (STC) we collected fMRI data from deaf and hearing participants (male and female), who either acquired sign language early or late in life. Our stimuli in all tasks were pictures of objects. We varied the linguistic and visuospatial processing demands in three different tasks that involved decisions about (1) the sublexical (phonological) structure of the British Sign Language (BSL) signs for the objects, (2) the semantic category of the objects, and (3) the physical features of the objects.Neuroimaging data revealed that in participants who were deaf from birth, STC showed increased activation during visual processing tasks. Importantly, this differed across hemispheres. Right STC was consistently activated regardless of the task whereas left STC was sensitive to task demands. Significant activation was detected in the left STC only for the BSL phonological task. This task, we argue, placed greater demands on visuospatial processing than the other two tasks. In hearing signers, enhanced activation was absent in both left and right STC during all three tasks. Lateralization analyses demonstrated that the effect of deafness was more task-dependent in the left than the right STC whereas it was more task-independent in the right than the left STC. These findings indicate how the absence of auditory input from birth leads to dissociable and altered functions of left and right STC in deaf participants.SIGNIFICANCE STATEMENT Those born deaf can offer unique insights into neuroplasticity, in particular in regions of superior temporal cortex (STC) that primarily respond to auditory input in hearing people. Here we demonstrate that in those deaf from birth the left and the right STC have altered and dissociable functions. The right STC was activated regardless of demands on visual processing. In contrast, the left STC was sensitive to the demands of visuospatial processing. Furthermore, hearing signers, with the same sign language experience as the deaf participants, did not activate the STCs. Our data advance current understanding of neural plasticity by determining the differential effects that hearing status and task demands can have on left and right STC function.

Clustered organization and region-specific identities of estrogen-producing neurons in the forebrain of Zebra Finches (Taeniopygia guttata).

A fast, neuromodulatory role for estrogen signaling has been reported in many regions of the vertebrate brain. Regional differences in the cellular distribution of aromatase (estrogen synthase) in several species suggest that mechanisms for neuroestrogen signaling differ between and even within brain regions. A more comprehensive understanding of neuroestrogen signaling depends on characterizing the cellular identities of neurons that express aromatase. Calcium-binding proteins such as parvalbumin and calbindin are molecular markers for interneuron subtypes, and are co-expressed with aromatase in human temporal cortex. Songbirds like the zebra finch have become important models to understand the brain synthesis of steroids like estrogens and the implications for neurobiology and behavior. Here, we investigated the regional differences in cytoarchitecture and cellular identities of aromatase-expressing neurons in the auditory and sensorimotor forebrain of zebra finches. Aromatase was co-expressed with parvalbumin in the caudomedial nidopallium (NCM) and HVC shelf (proper name) but not in the caudolateral nidopallium (NCL) or hippocampus. By contrast, calbindin was not co-expressed with aromatase in any region investigated. Notably, aromatase-expressing neurons were found in dense somato-somatic clusters, suggesting a coordinated release of local neuroestrogens from clustered neurons. Aromatase clusters were also more abundant and tightly packed in the NCM of males as compared to females. Overall, this study provides new insights into neuroestrogen regulation at the network level, and extends previous findings from human cortex by identifying a subset of aromatase neurons as putative inhibitory interneurons.

Differential proteome analysis of hippocampus and temporal cortex using label-free based 2D-LC-MS/MS

Hippocampus and temporal cortex are important brain regions, which play distinct, but complimentary roles in mediating learning and memory. Herein, we utilized label-free differential proteome strategy to explore function of normal human hippocampus and temporal cortex in learning and memory. As a result, a total of 5529 and 5702 proteins were identified in hippocampus and temporal cortex, respectively, 516 of which were significantly differential expressed, with abundance span 5 orders of magnitudes. Pathways analysis showed that temporal cortex was involved in growth of axons growth and synapse density regulation, through which could regulate long-term potentiation and long-term retention of trace memory. Hippocampus was involved in regulation of cell survival and cell viability, and regulates neurons proliferation by actin dynamics changes, through which involved in both short-term memory and long-term memory. Four selected differential proteins were further validated by Western blot and immunohistochemistry. For the first time, we identified proteins and associated pathways of hippocampus and temporal cortex in human cognition process using proteomic strategy, which would provide references for generating corresponding insights in hippocampus and temporal cortex-related cognitive function. The original data files can be downloaded at http://211.102.209.254/page/PSV023.html;?url=1489542083729AFHp (password: kYxh). SignificanceThis study explored the potential molecular mechanism of hippocampus and temporal cortex in human cognition function using proteomics strategy, which will offer a baseline reference for further cognitive disorders study and reveal insights into physiology of temporal cortex and hippocampus.

Domain Selectivity in the Parahippocampal Gyrus Is Predicted by the Same Structural Connectivity Patterns in Blind and Sighted Individuals.

Human ventral occipital temporal cortex contains clusters of neurons that show domain-preferring responses during visual perception. Recent studies have reported that some of these clusters show surprisingly similar domain selectivity in congenitally blind participants performing nonvisual tasks. An important open question is whether these functional similarities are driven by similar innate connections in blind and sighted groups. Here we addressed this question focusing on the parahippocampal gyrus (PHG), a region that is selective for large objects and scenes. Based on the assumption that patterns of long-range connectivity shape local computation, we examined whether domain selectivity in PHG is driven by similar structural connectivity patterns in the two populations. Multiple regression models were built to predict the selectivity of PHG voxels for large human-made objects from white matter (WM) connectivity patterns in both groups. These models were then tested using independent data from participants with similar visual experience (two sighted groups) and using data from participants with different visual experience (blind and sighted groups). Strikingly, the WM-based predictions between blind and sighted groups were as successful as predictions between two independent sighted groups. That is, the functional selectivity for large objects of a PHG voxel in a blind participant could be accurately predicted by its WM pattern using the connection-to-function model built from the sighted group data, and vice versa. Regions that significantly predicted PHG selectivity were located in temporal and frontal cortices in both sighted and blind populations. These results show that the large-scale network driving domain selectivity in PHG is independent of vision.SIGNIFICANCE STATEMENT Recent studies have reported intriguingly similar domain selectivity in sighted and congenitally blind individuals in regions within the ventral visual cortex. To examine whether these similarities originate from similar innate connectional roots, we investigated whether the domain selectivity in one population could be predicted by the structural connectivity pattern of the other. We found that the selectivity for large objects of a PHG voxel in a blind participant could be predicted by its structural connectivity pattern using the connection-to-function model built from the sighted group data, and vice versa. These results reveal that the structural connectivity underlying domain selectivity in the PHG is independent of visual experience, providing evidence for nonvisual representations in this region.

Category selectivity in human visual cortex: Beyond visual object recognition

Human ventral temporal cortex shows a categorical organization, with regions responding selectively to faces, bodies, tools, scenes, words, and other categories. Why is this? Traditional accounts explain category selectivity as arising within a hierarchical system dedicated to visual object recognition. For example, it has been proposed that category selectivity reflects the clustering of category-associated visual feature representations, or that it reflects category-specific computational algorithms needed to achieve view invariance. This visual object recognition framework has gained renewed interest with the success of deep neural network models trained to “recognize” objects: these hierarchical feed-forward networks show similarities to human visual cortex, including categorical separability. We argue that the object recognition framework is unlikely to fully account for category selectivity in visual cortex. Instead, we consider category selectivity in the context of other functions such as navigation, social cognition, tool use, and reading. Category-selective regions are activated during such tasks even in the absence of visual input and even in individuals with no prior visual experience. Further, they are engaged in close connections with broader domain-specific networks. Considering the diverse functions of these networks, category-selective regions likely encode their preferred stimuli in highly idiosyncratic formats; representations that are useful for navigation, social cognition, or reading are unlikely to be meaningfully similar to each other and to varying degrees may not be entirely visual. The demand for specific types of representations to support category-associated tasks may best account for category selectivity in visual cortex. This broader view invites new experimental and computational approaches.

Visual Field Map Clusters in High-Order Visual Processing: Organization of V3A/V3B and a New Cloverleaf Cluster in the Posterior Superior Temporal Sulcus.

The cortical hierarchy of the human visual system has been shown to be organized around retinal spatial coordinates throughout much of low- and mid-level visual processing. These regions contain visual field maps (VFMs) that each follows the organization of the retina, with neighboring aspects of the visual field processed in neighboring cortical locations. On a larger, macrostructural scale, groups of such sensory cortical field maps (CFMs) in both the visual and auditory systems are organized into roughly circular cloverleaf clusters. CFMs within clusters tend to share properties such as receptive field distribution, cortical magnification, and processing specialization. Here we use fMRI and population receptive field (pRF) modeling to investigate the extent of VFM and cluster organization with an examination of higher-level visual processing in temporal cortex and compare these measurements to mid-level visual processing in dorsal occipital cortex. In human temporal cortex, the posterior superior temporal sulcus (pSTS) has been implicated in various neuroimaging studies as subserving higher-order vision, including face processing, biological motion perception, and multimodal audiovisual integration. In human dorsal occipital cortex, the transverse occipital sulcus (TOS) contains the V3A/B cluster, which comprises two VFMs subserving mid-level motion perception and visuospatial attention. For the first time, we present the organization of VFMs in pSTS in a cloverleaf cluster. This pSTS cluster contains four VFMs bilaterally: pSTS-1:4. We characterize these pSTS VFMs as relatively small at ∼125 mm2 with relatively large pRF sizes of ∼2–8° of visual angle across the central 10° of the visual field. V3A and V3B are ∼230 mm2 in surface area, with pRF sizes here similarly ∼1–8° of visual angle across the same region. In addition, cortical magnification measurements show that a larger extent of the pSTS VFM surface areas are devoted to the peripheral visual field than those in the V3A/B cluster. Reliability measurements of VFMs in pSTS and V3A/B reveal that these cloverleaf clusters are remarkably consistent and functionally differentiable. Our findings add to the growing number of measurements of widespread sensory CFMs organized into cloverleaf clusters, indicating that CFMs and cloverleaf clusters may both be fundamental organizing principles in cortical sensory processing.

Developmental microglial priming in postmortem autism spectrum disorder temporal cortex

Microglia can shift into different complex morphologies depending on the microenvironment of the central nervous system (CNS). The distinct morphologies correlate with specific functions and can indicate the pathophysiological state of the CNS. Previous postmortem studies of autism spectrum disorder (ASD) showed neuroinflammation in ASD indicated by increased microglial density. These changes in the microglia density can be accompanied by changes in microglia phenotype but the individual contribution of different microglia phenotypes to the pathophysiology of ASD remains unclear. Here, we used an unbiased stereological approach to quantify six structurally and functionally distinct microglia phenotypes in postmortem human temporal cortex, which were immuno-stained with Iba1. The total density of all microglia phenotypes did not differ between ASD donors and typically developing individual donors. However, there was a significant decrease in ramified microglia in both gray matter and white matter of ASD, and a significant increase in primed microglia in gray matter of ASD compared to typically developing individuals. This increase in primed microglia showed a positive correlation with donor age in both gray matter and white of ASD, but not in typically developing individuals. Our results provide evidence of a shift in microglial phenotype that may indicate impaired synaptic plasticity and a chronic vulnerability to exaggerated immune responses.

The Cytoarchitecture of Domain-specific Regions in Human High-level Visual Cortex.

A fundamental hypothesis in neuroscience proposes that underlying cellular architecture (cytoarchitecture) contributes to the functionality of a brain area. However, this hypothesis has not been tested in human ventral temporal cortex (VTC) that contains domain-specific regions causally involved in perception. To fill this gap in knowledge, we used cortex-based alignment to register functional regions from living participants to cytoarchitectonic areas in ex vivo brains. This novel approach reveals 3 findings. First, there is a consistent relationship between domain-specific regions and cytoarchitectonic areas: each functional region is largely restricted to 1 cytoarchitectonic area. Second, extracting cytoarchitectonic profiles from face- and place-selective regions after back-projecting each region to 20-μm thick histological sections indicates that cytoarchitectonic properties distinguish these regions from each other. Third, some cytoarchitectonic areas contain more than 1 domain-specific region. For example, face-, body-, and character-selective regions are located within the same cytoarchitectonic area. We summarize these findings with a parsimonious hypothesis incorporating how cellular properties may contribute to functional specialization in human VTC. Specifically, we link computational principles to correlated axes of functional and cytoarchitectonic segregation in human VTC, in which parallel processing across domains occurs along a lateral–medial axis while transformations of information within domain occur along an anterior–posterior axis.

Unique membrane properties and enhanced signal processing in human neocortical neurons.

The advanced cognitive capabilities of the human brain are often attributed to our recently evolved neocortex. However, it is not known whether the basic building blocks of the human neocortex, the pyramidal neurons, possess unique biophysical properties that might impact on cortical computations. Here we show that layer 2/3 pyramidal neurons from human temporal cortex (HL2/3 PCs) have a specific membrane capacitance (Cm) of ~0.5 µF/cm2, half of the commonly accepted 'universal' value (~1 µF/cm2) for biological membranes. This finding was predicted by fitting in vitro voltage transients to theoretical transients then validated by direct measurement of Cm in nucleated patch experiments. Models of 3D reconstructed HL2/3 PCs demonstrated that such low Cm value significantly enhances both synaptic charge-transfer from dendrites to soma and spike propagation along the axon. This is the first demonstration that human cortical neurons have distinctive membrane properties, suggesting important implications for signal processing in human neocortex.

Gene expression analysis reveals the dysregulation of immune and metabolic pathways in Alzheimer's disease.

In recent years, several pathway analyses of genome-wide association studies reported the involvement of metabolic and immune pathways in Alzheimer's disease (AD). Until now, the exact mechanisms of these pathways in AD are still unclear. Here, we conducted a pathway analysis of a whole genome AD case-control expression dataset (n=41, 25 AD cases and 16 controls) from the human temporal cortex tissue. Using the differently expressed AD genes, we identified significant KEGG pathways related to metabolism and immune processes. Using the up- and down- regulated AD gene list, we further found up-regulated AD gene were significantly enriched in immune and metabolic pathways. We further compare the immune and metabolic KEGG pathways from the expression dataset with those from previous GWAS datasets, and found that most of these pathways are shared in both GWAS and expression datasets.

Dendritic-branching angles of pyramidal neurons of the human cerebral cortex

In this article, we analyze branching angles of the basal dendrites of pyramidal neurons of layers III and V of the human temporal cortex. For this, we use a novel probability directional statistical distribution called truncated von Mises distribution that is able to describe more accurately the dendritic-branching angles than the previous proposals. Then, we perform comparative studies using this statistical method to determine similarities and/or differences between branches and branching angles that belong to different cortical layers and regions. Using this methodology, we found that common design principles exist and govern the patterns found in the different branches that compose the basal dendrites of human pyramidal cells of the temporal cortex. However, particular differences were found between supra and infragranular cells. Furthermore, we compared the branching angles of human layer III pyramidal neurons with data obtained in the previous studies in layer III of both the rat somatosensory cortex and of several cortical areas of the mouse. Finally, we study the branching angle differences between the humans that compose our data.

Learning Warps Object Representations in the Ventral Temporal Cortex.

The human ventral temporal cortex (VTC) plays a critical role in object recognition. Although it is well established that visual experience shapes VTC object representations, the impact of semantic and contextual learning is unclear. In this study, we tracked changes in representations of novel visual objects that emerged after learning meaningful information about each object. Over multiple training sessions, participants learned to associate semantic features (e.g., "made of wood," "floats") and spatial contextual associations (e.g., "found in gardens") with novel objects. fMRI was used to examine VTC activity for objects before and after learning. Multivariate pattern similarity analyses revealed that, after learning, VTC activity patterns carried information about the learned contextual associations of the objects, such that objects with contextual associations exhibited higher pattern similarity after learning. Furthermore, these learning-induced increases in pattern information about contextual associations were correlated with reductions in pattern information about the object's visual features. In a second experiment, we validated that these contextual effects translated to real-life objects. Our findings demonstrate that visual object representations in VTC are shaped by the knowledge we have about objects and show that object representations can flexibly adapt as a consequence of learning with the changes related to the specific kind of newly acquired information.

Evaluation of the Nicotinic Acetylcholine Receptor-Associated Proteome at Baseline and Following Nicotine Exposure in Human and Mouse Cortex.

Nicotinic acetylcholine receptors (nAChRs) support the initiation and maintenance of smoking, but the long-term changes occurring in the protein complex as a result of smoking and the nicotine in tobacco are not known. Human studies and animal models have also demonstrated that increasing cholinergic tone increases behaviors related to depression, suggesting that the nAChR-associated proteome could be altered in individuals with mood disorders. We therefore immunopurified nAChRs and associated proteins for quantitative proteomic assessment of changes in protein–protein interactions of high-affinity nAChRs containing the β2 subunit (β2*-nAChRs) from either cortex of mice treated with saline or nicotine, or postmortem human temporal cortex tissue from tobacco-exposed and nonexposed individuals, with a further comparison of diagnosed mood disorder to control subjects. We observed significant effects of nicotine exposure on the β2*-nAChR-associated proteome in human and mouse cortex, particularly in the abundance of the nAChR subunits themselves, as well as putative interacting proteins that make up core components of neuronal excitability (Na/K ATPase subunits), presynaptic neurotransmitter release (syntaxins, SNAP25, synaptotagmin), and a member of a known nAChR protein chaperone family (14-3-3ζ). These findings identify candidate-signaling proteins that could mediate changes in cholinergic signaling via nicotine or tobacco use. Further analysis of identified proteins will determine whether these interactions are essential for primary function of nAChRs at presynaptic terminals. The identification of differences in the nAChR-associated proteome and downstream signaling in subjects with various mood disorders may also identify novel etiological mechanisms and reveal new treatment targets.

Hierarchy of prediction errors for auditory events in human temporal and frontal cortex

Predictive coding theories posit that neural networks learn statistical regularities in the environment for comparison with actual outcomes, signaling a prediction error (PE) when sensory deviation occurs. PE studies in audition have capitalized on low-frequency event-related potentials (LF-ERPs), such as the mismatch negativity. However, local cortical activity is well-indexed by higher-frequency bands [high-γ band (Hγ): 80-150 Hz]. We compared patterns of human Hγ and LF-ERPs in deviance detection using electrocorticographic recordings from subdural electrodes over frontal and temporal cortices. Patients listened to trains of task-irrelevant tones in two conditions differing in the predictability of a deviation from repetitive background stimuli (fully predictable vs. unpredictable deviants). We found deviance-related responses in both frequency bands over lateral temporal and inferior frontal cortex, with an earlier latency for Hγ than for LF-ERPs. Critically, frontal Hγ activity but not LF-ERPs discriminated between fully predictable and unpredictable changes, with frontal cortex sensitive to unpredictable events. The results highlight the role of frontal cortex and Hγ activity in deviance detection and PE generation.

Frequency-Selective Attention in Auditory Scenes Recruits Frequency Representations Throughout Human Superior Temporal Cortex.

A sound of interest may be tracked amid other salient sounds by focusing attention on its characteristic features including its frequency. Functional magnetic resonance imaging findings have indicated that frequency representations in human primary auditory cortex (AC) contribute to this feat. However, attentional modulations were examined at relatively low spatial and spectral resolutions, and frequency-selective contributions outside the primary AC could not be established. To address these issues, we compared blood oxygenation level-dependent (BOLD) responses in the superior temporal cortex of human listeners while they identified single frequencies versus listened selectively for various frequencies within a multifrequency scene. Using best-frequency mapping, we observed that the detailed spatial layout of attention-induced BOLD response enhancements in primary AC follows the tonotopy of stimulus-driven frequency representations-analogous to the "spotlight" of attention enhancing visuospatial representations in retinotopic visual cortex. Moreover, using an algorithm trained to discriminate stimulus-driven frequency representations, we could successfully decode the focus of frequency-selective attention from listeners' BOLD response patterns in nonprimary AC. Our results indicate that the human brain facilitates selective listening to a frequency of interest in a scene by reinforcing the fine-grained activity pattern throughout the entire superior temporal cortex that would be evoked if that frequency was present alone.